Growth is essential for cell proliferation and differentiation in all organisms and causes a wide range of severe human diseases if misregulated. Cell surface growth relies critically on coordinated delivery of membranes and proteins to the cell periphery via the secretory pathway. Although this phenomenon has been recognized for several decades, it remains unknown how the biosynthetic pathway is regulated in response to growth signaling. Phosphorylated lipids have been recently implicated in regulating cell growth-specific processes. Based on our preliminary evidence, we propose a central role for phosphoinositide lipids in growth regulation of secretion. While it is established that phosphoinositides are essential for intracellular membrane traffic, a link between lipid signaling within the biosynthetic pathway and cell growth has not been characterized. In this proposal, we aim to demonstrate a novel and essential role for the SAC1 lipid phosphatase in the regulation of the secretory pathway during cell growth. Our preliminary studies show that human SAC1 shuttles between endoplasmic reticulum (ER) and Golgi in response to growth conditions and regulates lipid signaling at these organelles. Our goal is to elucidate the mechanism of growth-dependent shuttling of SAC1 and to analyze the role of SAC1 in secretion and cell proliferation. We will investigate these questions in three distinct aims. Specifically, we will characterize the growth-regulated mechanism of SAC1 translocation between ER and Golgi. We will analyze how SAC1 regulates phosphoinositides at ER and Golgi and how this regulation relates to organellar function and trafficking. Finally we will identify the mitogen-dependent signaling pathway that controls SAC1 localization and we will examine how this process is related to growth stimulation of quiescent cells and to tumor cell growth. Characterization of the molecular mechanisms that integrate secretion and cell growth will lead to the identification of novel classes of drugs targets and eventually help preventing diseases stemming from abnormal cell proliferation. PUBLIC HEALTH RELEVANCE: Defects in phosphoinositide signaling cause human disease including cancer, diabetes and kidney disease. Characterization of the phosphoinositide-based regulation that integrates secretion and cell growth will facilitate identification of novel drug targets to prevent or cure such diseases.